ArticleNature communications2025
Perimenopausal state oestradiol to progesterone imbalance drives Alzheimer's risk via ERRα dysregulation and energy dyshomeostasis.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
2 citing papers in PubMed.
- The Neurology of Menopause.Current neurology and neuroscience reports · 2026Review
- The APOE4-estrogen-microglia axis in perimenopausal cognitive changes: mechanisms and therapeutic implications.Frontiers in immunology · 2026Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors.
Funding
Abstract
Sex-biased differences in Alzheimer's disease (AD) are well documented, but the mechanisms underlying increased vulnerability in postmenopausal women remain unclear. This study aimed to model the effects of perimenopausal hormonal fluctuations on AD pathophysiology. Using a VCD-induced accelerated ovarian failure model in young female C57BL/6 J and 3xTg mice, we simulated a perimenopausal state with hormonal changes characterised by elevated oestradiol levels and reduced progesterone levels. Supporting human brain transcriptomic and metabolomic data from the ROSMAP study revealed that impaired oestrogen-related receptor alpha (ERRα) function was a key driver of female sex-biased vulnerability. In female mice, progesterone-guided oestrogen receptor signalling maintained ERRα activity by regulating neuronal cholesterol homoeostasis and the TCA cycle. Hormonal imbalances disrupted this mechanism, triggering an aspartate-driven "minicycle," which increased glutamate release, neuronal excitability, ATP depletion, and energy crisis susceptibility. This study demonstrates how perimenopausal hormonal imbalances exacerbate AD risk via ERRα dysfunction, linking neuronal cholesterol and energy homeostasis to disease vulnerability.
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Registered trials
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